BACKGROUND: Impairment in 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) activity results in inefficient inactivation of cortisol to cortisone, and it can trigger hypertension through activation of the mineralocorticoid receptor. Information about age-related changes in 11ß-HSD2 activity and its physiological consequences is scarce. Our aim was to investigate whether 11ß-HSD2 activity is age dependent in normotensive subjects. METHODS: We recruited 196 healthy, normotensive subjects. Of these, 93 were children (Group 1: aged 5-15 years), and 103 were adults who were divided according to their ages: Group 2: aged 30-41 years (n = 10); Group 3: aged 42-53 years (n = 72); and Group 4: aged 54-65 years (n = 21). Fasting serum cortisol, cortisone, aldosterone, and plasma renin activity (PRA) were measured. The 11ß-HSD2 activity was estimated by the cortisol/cortisone ratio. The results were expressed as median (interquartile range (IQR)) values and compared using Kruskal-Wallis and Dunn's multiple-comparison tests. RESULTS: As subject age increased, cortisol concentrations increased (Group 1 median = 8.6, IQR = 6.3-10.8 µg/dl; Group 4 median = 12.4, IQR = 10.7-14.7 µg/dl; P < 0.001), and cortisone concentrations showed a gradual decrease (Group 2 median = 4.0, IQR = 3.3-4.2 µg/dl; Group 4 median =2.8, IQR = 2.6-3.3 µg/dl; P < 0.01). As a consequence, the cortisol/cortisone ratio was higher in the oldest subjects (Group 4) than in the subjects from the other 3 groups; the ratios from Group 4 to Group 1 were 4.4 (IQR = 3.7-5.1) µg/dl, 3.3 (IQR = 2.7-3.8) µg/dl, 2.5 (IQR = 2.3-3.8) µg/dl, and 2.7 (IQR = 2.1-3.4) µg/dl, respectively (P < 0.01). The PRA decreased with age. Blood pressure levels increased with age but stayed within the normal range. CONCLUSIONS: Cortisol and the cortisol/cortisone ratio increased with age, but cortisone decreased, suggesting a decrease in 11ß-HSD2 activity. These results suggest that the cortisol-mediated activation of the mineralocorticoid receptor may explain the blood pressure increase in elderly subjects.